SCIENTISTS TRYING TO SORT GENES TO CREATE NEW LIFE

In a bold effort to learn one of nature's most impenetrable secrets, a team of prominent molecular biologists is trying to create life from scratch, spawning dramatic ethical questions in the process.

Their strategy is to discover the minimum number of genes necessary to keep the simplest known bacterium alive, make synthetic copies of those genes, assemble them and then see if they spark life.

Led by J. Craig Venter of the private Institute for Genomic Research in Rockville, Md., the researchers have taken the first step: sifting through the genes of the bacterium to find a set absolutely essential for its life. Their results are published in Friday's issue of the journal Science.

Experts say that decades from now knowledge from such projects could give human scientists one of the ultimate powers of creation--the ability to design and construct novel species and forms of life from the bottom up. The possible result would be nothing less than a redefinition of what constitutes life.

Although experts agree such advances are a long way off if possible at all, the research and its potential long-term applications present an ethical nightmare.

Venter's main concern is that nations could exploit technology from the project to invent new biological weapons. That fear alone has been enough for the team to suspend its efforts to create a new organism and ask one of the nation's pre-eminent ethicists to help them decide how or whether to continue.

There's also a question of commercialism. Venter is president of the biotech company Celera Genomics, which stands to profit if the technology yields new genetic patents.

The work done so far is impressive even to researchers from the federal agency that is competing with Venter's group on the separate task of decoding the human genome.

"The possibility of engineering artificial cells based on this knowledge would be a neat trick," said Elke Jordan, deputy director of the National Center for Human Genome Research.

"If you have control of the whole system and you can put it together artificially and take it apart, that might be something that would be of great utility," she said.

Venter's team had studied their bacterium enough to begin seriously contemplating a fateful step two years ago. They wanted to see if they could fashion a "synthetic chromosome" based on a minimal set of genes, then inject it into a specially prepared bacterial cell.

But then they stopped.

"We realized we sort of had blinders on and were just thinking about the experiment and how to do it," Venter said. "But if we were successful, there would be far broader implications of our work and how it might be used."

So the team asked Arthur Caplan, director of the Center for Bioethics at the University of Pennsylvania, to assemble 15 ethicists and theologians to look at the issues raised by the research and give recommendations.

"The real purpose of this is asking the big, fundamental questions we all like to ask," Venter said. "What is life? Can we define it at the molecular level? Can we start to understand how evolution took place, how life originated?"

The suspension of work toward synthesizing organisms allows more time for pondering implications of the research, a rare luxury when discoveries in fields such as cloning and genetic engineering often are made and become commercial products before the public can debate their impact.

For example, would the ability to create new organisms affect beliefs about the sacredness of life? Would such power necessarily imply that life's mystery consists of nothing more than the brew of genes and chemicals in our cells?

One of the new study's major findings is a humbling illustration of how distant the goal of synthesizing life remains. Among the 300 or so genes necessary to keep the bacterium alive, scientists have no clue as to what 100 of them do.

"That's pretty sobering," Venter said. "It tells us we don't know all that much about biology. If we can't understand a minimal cell with 300 genes, what hope do we have of understanding our own 100 trillion cells, each with 80,000 different genes in them?"

M. genitalium, the microbe at the center of the research effort, is a human parasite that appears to be relatively harmless.

Venter's team reported in Science that it has winnowed down the number of genes necessary to keep the bacterium alive from the full complement of 517 to between 265 and 350.

While it is widely believed that evolution moves forward by adding new genes to an organism, M. genitalium shows that evolution also works by removing excess genes.

The pursuit of its bare-bones complement of genes is important because most of the genes it needs to live are shared by other creatures, including humans.

The team made another discovery confirming that one of the long-held tenets of genetics is wrong. Instead of a gene making one protein to perform only one job, it can make different proteins that do different jobs.

"That's a central dogma of biology, which is absolutely wrong," Venter said. "If biology worked that way, we would not exist as a species."

Understanding the minute workings of such an organism has potentially beneficial applications. It could lead to simple ways of genetically engineering bacteria so that they can perform a wide variety of tasks, such as making new drugs and vaccines, and creating microbes tailored to eat pollution and radioactive wastes.

The theologians and ethicists assembled by Caplan published their conclusions in an editorial accompanying Venter's study in Science. They had worked for nearly two years under a grant from Celera, yet Caplan said they were independent of the company.

Some of the group's recommendations clashed with Venter's positions. For example, the ethicists proposed a "new regulatory framework" to ensure that commercial gene patents do not stifle basic genetic research, a change Venter said he opposes.

Many of the problems the panel addressed have never been systematically explored, Caplan said. During a press conference Thursday, Venter recounted the occasion two years ago when he first asked Caplan whether it would be ethical to synthesize life in the laboratory.

Ultimately, Caplan's group concluded there is no ethical reason not to try to create artificial life.

"There are many people who are going to say, `Don't do this because it's playing God,' " Caplan said. "We tried to wrestle with that question, and our theologians basically said that's not an argument, that's just an assertion."

The Judeo-Christian tradition in general accepts the principle that people inevitably will disrupt nature, Caplan said.

"The argument is not so much that man should not intervene in nature, but that it really matters what you're doing it for," Caplan said. "Whether access to the benefits are fair and the distribution of any burden is fair."

Caplan's group did not specifically endorse the goal of synthesizing life. Caplan said the priority should be to lay out rules that guard against the misuse of such technology--preferably now, before the science is done.

One goal of any new rules should be to prevent the development of new germs for biological warfare, Caplan said. Venter said Thursday that his group will not try to develop synthetic chromosomes until increased safeguards against such warfare have been developed.

A more nagging problem may be the effect of such work on how people view life.

Caplan's group of ethicists was concerned that the public might interpret the successful synthesis of life as dispiriting proof that life is "nothing more than DNA." But there are many different ways to define life, they noted.

"At least since Aristotle, there has been a tradition that sees life as something more than merely physical," the group wrote. "This provides the basis for belief in the interconnectedness of all living things and the sense that living things are, in some important way, more than organized matter."